WO2007024876A2 - Methodes de traitement et de surveillance de l'inflammation et du desequilibre d'oxydoreduction dans la mucoviscidose - Google Patents

Methodes de traitement et de surveillance de l'inflammation et du desequilibre d'oxydoreduction dans la mucoviscidose Download PDF

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WO2007024876A2
WO2007024876A2 PCT/US2006/032809 US2006032809W WO2007024876A2 WO 2007024876 A2 WO2007024876 A2 WO 2007024876A2 US 2006032809 W US2006032809 W US 2006032809W WO 2007024876 A2 WO2007024876 A2 WO 2007024876A2
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acetylcysteine
pharmaceutically acceptable
pharmaceutical composition
per day
container
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PCT/US2006/032809
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WO2007024876A3 (fr
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Rabindra Tirouvanziam
Lenore A. Herzenberg
Leonard A. Herzenberg
Carol Conrad
Richard B. Moss
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The Board Of Trustees Of Leland Stanford Junior University
Thiolex Development Corp.
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Priority to CA2620123A priority Critical patent/CA2620123C/fr
Publication of WO2007024876A2 publication Critical patent/WO2007024876A2/fr
Publication of WO2007024876A3 publication Critical patent/WO2007024876A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to pharmaceutical kits and methods for treating lung inflammation and redox imbalance conditions in cystic fibrosis using pharmaceutical compositions comprising N-acetylcysteine, pharmaceutically acceptable salts of N- acetylcysteine, or pharmaceutically acceptable derivatives of N-acetylcysteine and a pharmaceutically acceptable carrier.
  • a free radical is a highly reactive and usually short-lived molecular fragment with one or more unpaired electrons. Free radicals are highly chemically reactive molecules. Because a free radical needs to extract a second electron from a neighboring molecule to pair its single electron, it often reacts with other molecules, which initiates the formation of many more free radical species in a self-propagating chain reaction. This ability to be self- propagating makes free radicals highly toxic to living organisms.
  • ROS Reactive oxygen species
  • Oxygen radicals such as the hydroxyl radical (OH " ) and the superoxide ion (O 2 " ) are very powerful oxidizing agents and cause structural damage to proteins, lipids and nucleic acids.
  • the free radical superoxide anion a product of normal cellular metabolism, is produced mainly in mitochondria because of incomplete reduction of oxygen.
  • the superoxide radical although unreactive compared with many other radicals, can be converted by biological systems into other more reactive species, such as peroxyl (ROO-), alkoxyl (RO-) and hydroxyl (OH-) radicals.
  • the major cellular sources of free radicals under normal physiological conditions are the mitochondria and inflammatory cells, such as granulocytes, macrophages, and some T-lymphocytes, which produce active species of oxygen via the nicotinamide adenine nucleotide oxidase (NADPH oxidase) system, as part of the body's defense against bacterial, fungal or viral infections.
  • mitochondria and inflammatory cells such as granulocytes, macrophages, and some T-lymphocytes, which produce active species of oxygen via the nicotinamide adenine nucleotide oxidase (NADPH oxidase) system, as part of the body's defense against bacterial, fungal or viral infections.
  • NADPH oxidase nicotinamide adenine nucleotide oxidase
  • Oxidative injury can lead to widespread biochemical damage within the cell.
  • the molecular mechanisms responsible for this damage are complex.
  • free radicals can damage intracellular macromolecules, such as nucleic acids (e.g., DNA and RNA), proteins, and lipids.
  • Free radical damage to cellular proteins can lead to loss of enzymatic function and cell death.
  • Free radical damage to DNA can cause problems in replication or transcription, leading to cell death or uncontrolled cell growth.
  • Free radical damage to cell membrane lipids can cause the damaged membranes to lose their ability to transport oxygen, nutrients or water to cells.
  • Biological systems protect themselves against the damaging effects of activated species by several means. These include free radical scavengers and chain reaction terminators; "solid-state” defenses, and enzymes, such as superoxide dismutase, catalase, and the glutathione peroxidase system.
  • Free radical scavengers/chemical antioxidants such as vitamin C and vitamin E, counteract and minimize free radical damage by donating or providing unpaired electrons to a free radical and converting it to a nonradical form. Such reducing compounds can terminate radical chain reactions and reduce hydroperoxides and epoxides to less reactive derivatives.
  • sold state defense refers to the mechanism whereby a macromolecule binds a radical-generating compound, de-excites an excited state species, or quenches a free radical.
  • the most important solid-state defense in the body is the black pigment melanin, which scavenges odd electrons to form stable radical species, thus terminating radical chain reactions.
  • Enzymatic defenses against active free radical species include superoxide dismutase, catalases, and the glutathione reductase/peroxidase system.
  • Superoxide dismutase (SOD) is an enzyme that destroys superoxide radicals.
  • Catalase a heme-based enzyme which catalyses the breakdown of hydrogen peroxide into oxygen and water, is found in all living cells, especially in the peroxisomes, which, in animal cells, are involved in the oxidation of fatty acids and the synthesis of cholesterol and bile acids.
  • Hydrogen peroxide is a byproduct of fatty acid oxidation and is produced by white blood cells to kill bacteria.
  • Glutathione a tripeptide composed of glycine, glutamic acid, and cysteine that contains a nucleophilic thiol group
  • GSH reduced thiol form
  • GSSG oxidized disulfide form
  • glutathione acts as a substrate for the enzymes GSH-S-transferase and GSH peroxidase, both of which catalyze reactions for the detoxification of xenobiotic compounds, and for the antioxidation of reactive oxygen species and other free radicals.
  • xenobiotic is used herein to refer to a chemical that is not a natural component of the organism exposed to it.
  • xenobiotics include, but are not limited to, carcinogens, toxins and drugs.
  • the metabolism of xenobiotics usually involves two distinct stages. Phase I metabolism involves an initial oxidation, reduction or dealkylation of the xenobiotic by microsomal cytochrome P-450 monooxygenases (Guengerich, F.P. Chem. Res. Toxicol. 4: 391-407 (1991)); this step often is needed to provide hydroxyl- or amino groups, which are essential for phase II reactions.
  • Glutathione detoxifies many highly reactive intermediates produced by cytochrome P450 enzymes in phase I metabolism. Without adequate GSH, the reactive toxic metabolites produced by cytochrome P-450 enzymes may accumulate causing organ damage.
  • Phase II metabolism generally adds hydrophilic moieties, thereby making a toxin more water soluble and less biologically active. Frequently involved phase II conjugation reactions are catalyzed by glutathione S-transferases (Beckett, GJ. & Hayes, J.D., Adv. Clin. Chem. 30: 281-380 (1993)), sulfotransferases (Falany, CN, Trends Pharmacol. Sci. 12: 255- 59 (1991)), and UDP-glucuronyl-transferases (Bock, KW, Crit. Rev. Biochem. MoI. Biol. 26: 129-50 (1991)).
  • Glutathione S-transferases catalyze the addition of aliphatic, aromatic, or heterocyclic radicals as well as epoxides and arene oxides to glutathione. These glutathione conjugates then are cleaved to cysteine derivatives primarily by renal enzymes and then acetylated, thus forming N-acetylcysteine derivatives.
  • Examples of compounds transformed to reactive intermediates and then bound to GSH include, but are not limited to, bromobenzene, chloroform, and acetaminophen. Such toxicants may deplete GSH. [0013] Depletion of GSH can diminish the body's ability to defend against lipid peroxidation.
  • Glutathione peroxidase an enzyme of the oxidoreductase class, catalyzes the detoxifying reduction of hydrogen peroxide and organic peroxides via oxidation of glutathione.
  • GSH is oxidized to the disulfide linked dimer (GSSG), which is actively pumped out of cells and becomes largely unavailable for reconversion to reduced glutathione.
  • GSH also is a cofactor for glutathione peroxidase. Thus, unless glutathione is resynthesized through other pathways, utilization of oxidized glutathione is associated with a reduction in the amount of glutathione available.
  • Glutathione reductase (NADPH), a flavoprotein enzyme of the oxidoreductase class, is essential for the maintenance of cellular glutathione in its reduced form (Carlberg & Mannervick, J. Biol. Chem. 250: 5475-80 (1975)). It catalyzes the reduction of oxidized glutathione (GSSG) to reduced glutathione (GSH) in the presence of NADPH and maintains a high intracellular GSH/GSSG ratio of about 500:1 in red blood cells.
  • GSSG oxidized glutathione
  • GSH reduced glutathione
  • Synthesis of GSH requires cysteine, a conditionally essential amino acid that must be obtained from dietary sources or by conversion of dietary methionine via the cystathionase pathway.
  • GSH depletion occurs if supplies of cysteine are inadequate to maintain GSH homeostasis in the face of increased GSH consumption.
  • Acute GSH depletion causes severe ⁇ often fatal-- oxidative and/or alkylation injury, and chronic or slow arising GSH deficiency due to administration of GSH-depleting drugs, such as acetaminophen, or to diseases and conditions that deplete GSH, can be similarly debilitating.
  • Cysteine is necessary to replenish hepatocellular GSH.
  • NAC N-acetyl cysteine
  • Glutathione, glutathione monoethyl ester, and L-2-oxothiazolidine-4-carboxylate (procysteine/OTC) also have been used effectively in some studies, hi addition, dietary methionine and S-adenosylmethionine are an effective source of cysteine.
  • NACs scavenger function it is well-known that NAC promotes cellular glutathione production, and thus reduces, or even prevents, oxidant mediated damage. Indeed, treatment with NAC provides beneficial effects in a number of respiratory, cardiovascular, endocrine, infectious, and other disease settings as described in WO05/017094, the contents of which are incorporated by reference herein.
  • rapid administration of NAC is the standard of care for preventing hepatic injury in acetaminophen overdose.
  • NAC administered intravenously in dogs has been shown to protect against pulmonary oxygen toxicity and against ischemic and reperfusion damage [Gillissen, A., andNowak, A., Respir. Med.
  • NAC also has antiinflammatory properties. Id.
  • ARDS acute respiratory distress syndrome
  • IPF idiopathic pulmonary fibrosis
  • COPD chronic obstructive pulmonary disorder
  • 5,824,693 discloses a method for treating ARDS and infant respiratory distress syndrome (IRDS), which result in oxidative stress that can damage the cells of the lung.
  • the method increases the intracellular synthesis of glutathione by administering a noncysteine glutathione precursor that will stimulate the intracellular synthesis of glutathione.
  • Cystic fibrosis is an inherited autosomal recessive disorder. It is one of the most common fatal genetic disorders in the United States, affecting about 30,000 individuals and is most prevalent in the Caucasian population, occurring in one of every 3,300 live births.
  • the gene involved in cystic fibrosis which was identified in 1989, codes for a protein called the cystic fibrosis transmembrane conductance regulator (CFTR).
  • CFTR cystic fibrosis transmembrane conductance regulator
  • cystic fibrosis patients mutations in the CFTR gene lead to alterations or total loss of CFTR protein function, resulting in defects in osmolality, pH and redox properties of exocrine secretions.
  • CF manifests itself by the presence of a thick mucus secretion which clogs the airways.
  • CF may not manifest itself by an obstructive phenotype, but rather by abnormal salt composition of the secretions (hence the clinical sweat osmolality test used to identify CF in patients).
  • the predominant cause of illness and death in cystic fibrosis patients is progressive lung disease.
  • CF mucus which blocks the airway passages, is believed to stem from abnormalities in osmolality of secretions, as well as from the presence of massive amounts of DNA, actin, proteases and prooxidative enzymes originating from a subset of inflammatory cells, called neutrophils. Indeed, CF lung disease is characterized by early, hyperactive neutrophil-mediated inflammatory reactions to both viral and bacterial pathogens.
  • the hyperinflammatory syndrome of CF lungs has several underpinnings, among which an imbalance between pro-inflammatory chemokines, chiefly interleukin-8 (IL-8), and antiinflammatory cytokines, chiefly IL-10, seems to play a major role.
  • IL-8 pro-inflammatory chemokines
  • IL-10 antiinflammatory cytokines
  • chronic oxidative stress in CF patients may severely affect the deformability of blood neutrophils circulating in CF lung capillaries, thereby increasing their recruitment to the lungs.
  • Hogg Physiol Rev. 67(4): 1249-95 (1987).
  • oxidative stress in CF is linked to the overwhelming release of oxidants by inflammatory lung neutrophils, and to abnormal antioxidant defenses caused by malabsorption of dietary antioxidant through the gut and a possible defect in GSH efflux. See Wood et al. J. Am. Coll. Nutr. 20(2 Suppl): 157-165 (2001).
  • the hyperinflammatory syndrome at play in CF lungs may predispose such patients to chronic infections with colonizing bacterial pathogens.
  • the most common bacterium to infect the CF lung is Pseudomonas aeruginosa, a gram-negative microorganism.
  • the lungs of most children with CF become colonized by P. aeruginosa before their third birthday.
  • P. aeruginosa becomes dominant over other opportunistic pathogens. See Gibson et al., Am. J. Respir. Crit Care Med., 168(8): 918-951 (2003). P. aeruginosa infections further exacerbate neutrophilic inflammation, which causes repeated episodes of intense breathing problems in CF patients. Although antibiotics can decrease the frequency and duration of these attacks, the bacterium progressively establishes a permanent residence in CF lungs by switching to a so-called "mucoid", biofilm form of high resistance and low virulence, which never can be eliminated completely from the lungs.
  • Treatments for CF lung disease typically involve antibiotics, anti-inflammatory drugs, bronchodilators, and chest physiotherapy to help fight infection, neutrophilic inflammation and obstruction and clear the airways. Nevertheless, the persistent, viscous and toxic nature of airway secretions in cystic fibrosis lung disease still leads to progressive deterioration of lung function. See Rancourt et al., Am. J. Physiol. Lung Cell MoI. Physiol. 286(5): L931-38 (2004).
  • NAC N-acetylcysteine
  • NACs antioxidant properties could be useful in preventing decline of lung function (defined as forced expiratory volume in one second, or FEV 1 , meaning the volume of air that can be exhaled during the first second of a forced exhalation, which is a reflection of the flow of air in the large airways of the lung) in cystic fibrosis by performing a systematic review of the literature to evaluate whether published evidence supports the use of NAC administered orally or by nebulization to improve lung function in patients with cystic fibrosis. They identified 23 papers, the majority of which were uncontrolled clinical observations, of which only three randomized controlled trials on nebulized NAC were found. None of these studies showed a statistically significant or clinically relevant beneficial effect of NAC aerosol.
  • the present invention relates to N-acetylcysteine compositions and methods to treat lung inflammation and redox imbalance conditions in human cystic fibrosis patients.
  • the present invention provides a method of treating a lung inflammation condition in cystic fibrosis patients, the method comprising the step of administering to a patient in need thereof a pharmaceutical composition comprising an inflammation-reducing amount of N- acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine, and a pharmaceutically acceptable carrier, thereby modulating the lung inflammation.
  • the lung inflammation condition is acute or chronic, hi another embodiment, in step (a) of the method, the pharmaceutical composition is administered systemically by a route selected from the group consisting of orally, buccally, topically, by inhalation, by insufflation, parenterally and rectally.
  • the pharmaceutical composition is administered orally.
  • the inflammation-reducing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition administered orally is about 1.8 grams per day to about 6 grams per day, and less than or equal to 70 mg/kg/d.
  • the inflammation-reducing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N- acetylcysteine in the pharmaceutical composition administered orally is at least about 1800 mg per day and less than or equal to 70 mg/kg/d. In another embodiment, the inflammation- reducing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetyl cysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition administered orally is at least about 2400 mg per day and less than or equal to 70 mg/kg/d.
  • the inflammation-reducing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition administered orally is at least about 3000 mg per day and less than or equal to 70 mg/kg/d.
  • the pharmaceutical composition is administered parenterally.
  • the inflammation-reducing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N- acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition administered parenterally is about 200 mg NAC to about 20000 mg NAC per dosage unit.
  • the method further comprises the step of administering a pharmaceutically effective amount of a cystic fibrosis therapeutic agent.
  • the cystic fibrosis therapeutic agent is at least one agent selected from the group consisting of an anti-infective agent, a bronchodilating agent, and an antiinflammatory agent.
  • the method further comprises the step of administering a respiratory therapy to the patient.
  • the method further comprises the step of administering a rehabilitation therapy to the patient.
  • the method further comprises the step of monitoring lung function of the patient.
  • the method further comprises the step of monitoring the lung inflammation by a method comprising the steps of: collecting a sample of blood or sputum from the patient; and determining a measure of inflammatory, activity in the blood or sputum collected from the patient, hi another embodiment, the measure of inflammatory activity in the sample of blood is at least one measure selected from the group consisting of a plasma level of neutrophil elastase activity and a plasma level of interleukin-8 activity, hi another embodiment, the measure of inflammatory activity in the sample of sputum is at least one measure selected from the group consisting of a count of live leukocytes, a count of live neutrophils, a ratio of neutrophils to total leukocytes; a sputum level of neutrophil elastase activity and a sputum level of interleukin-8 activity.
  • the present invention further provides a method of treating a redox imbalance condition in cystic fibrosis patients, the method comprising the step of administering to a patient in need thereof a pharmaceutical composition comprising a redox-balancing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine, and a pharmaceutically acceptable carrier, thereby modulating the redox imbalance condition.
  • the pharmaceutical composition is administered systemically by a route selected from the group consisting of orally, buccally, parenterally, topically, by inhalation, by insufflation, and rectally.
  • the pharmaceutical composition is administered orally.
  • the redox-balancing amount of N- acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition administered orally is about 1.8 grams per day to about 6 grams per day and less than or equal to 70 mg/kg/d.
  • the redox-balancing amount of N- acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition administered orally is at least about 1800 mg per day and less than or equal to 70 mg/kg/d. According to another embodiment, the redox-balancing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N- acetylcysteine in the pharmaceutical composition administered orally is at least about 2400 mg per day and less than or equal to 70 mg/kg/d.
  • the redox-balancing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N- acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition administered orally is at least about 3000 mg per day and less than or equal to 70 mg/kg/d.
  • the pharmaceutical composition is administered parenterally.
  • the redox-balancing amount of N- acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition administered parenterally is about 200 mg NAC to about 20000 mg NAC per dosage unit.
  • the method further comprises the step of administering a pharmaceutically effective amount of a cystic fibrosis therapeutic agent.
  • the cystic fibrosis therapeutic agent is at least one agent selected from the group consisting of an anti-infective agent, a bronchodilating agent, and an antiinflammatory agent.
  • the method further comprises the step of administering a respiration therapy to the patient.
  • the method further comprises the step of administering a rehabilitative therapy to the patient.
  • the method further comprises the step of monitoring lung function of the patient.
  • the method further comprises the step of monitoring the redox imbalance in cystic fibrosis patients by a method comprising the steps of collecting a sample of blood or sputum from the patient; and determining a measure of redox balance in the sample of blood or sputum.
  • the measure of redox balance in the sample of blood is at least one measure selected from the group consisting of a level of reduced glutathione in whole blood and a level of reduced glutathione in live blood neutrophils.
  • the present invention provides a pharmaceutical kit for treating a lung inflammation condition in cystic fibrosis patients, the kit comprising a first container containing a pharmaceutically effective amount of a cystic fibrosis therapeutic agent, and a second container containing a pharmaceutical composition comprising an inflammation- reducing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition in the second container is to be administered systemically by a route selected from the group consisting of orally, buccally, parenterally, topically, by inhalation, by insufflation, or rectally.
  • the pharmaceutical composition in the second container is administered orally.
  • the pharmaceutical composition to be administered orally that is in the second container is in an oral form selected from the forms consisting of a tablet, a troche, a lozenge, an aqueous suspension, an oily suspension, a dispersible powder, a dispersible granule, an emulsion, a hard capsule, a soft capsule, a syrup, and an elixir.
  • the inflammation- reducing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition to be administered orally that is in the second container is about 1.8 grams per day to about 6 grams per day, and less than or equal to 70 mg/kg/d.
  • the inflammation-reducing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N- acetylcysteine in the pharmaceutical composition to be administered orally that is in the second container is at least about 1800 mg per day and less than or equal to 70 mg/kg/d.
  • the inflammation-reducing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition to be administered orally that is in the second container is at least about 2400 mg per day and less than or equal to 70 mg/kg/d.
  • the inflammation-reducing amount of N- acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition to be administered orally that is in the second container is at least about 3000 mg per day and less than or equal to 70 mg/kg/d.
  • the pharmaceutical composition in the second container is to be administered parenterally.
  • the inflammation-reducing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N- acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition to be administered parenterally that is in the second container is about 200 mg NAC to about 20000 mg NAC per dosage unit.
  • the cystic fibrosis therapeutic agent in the first container is at least one agent selected from the group consisting of an anti-infective agent, a bronchodilating agent, and an anti-inflammatory agent.
  • the present invention provides a pharmaceutical kit for treating a redox imbalance condition in cystic fibrosis patients, the kit comprising a first container containing a pharmaceutically effective amount of a cystic fibrosis therapeutic agent, and a second container containing a pharmaceutical composition comprising a redox-balancing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition in the second container is to be administered systemically by a route selected from the group consisting of orally, buccally, parenterally, topically, by inhalation, by insufflation, or rectally.
  • the pharmaceutical composition in the second container is to be administered orally
  • the pharmaceutical composition to be administered orally that is in the second container is in a form selected from the forms consisting of a tablet, a troche, a lozenge, an aqueous suspension, an oily suspension, a dispersible powder, a dispersible granule, an emulsion, a hard capsule, a soft capsule, a syrup, and an elixir
  • the redox-balancing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition to be administered orally that is in the second container is
  • the redox-balancing amount of N- acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition to be administered orally that is in the second container is at least about 1800 mg per day and less than or equal to 70 mg/kg/d.
  • the redox-balancing amount of N- acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition to be administered orally that is in the second container is at least about 2400 mg per day and less than or equal to 70 mg/kg/d.
  • the redox-balancing amount of N- acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition to be delivered orally that is in the second container is at least about 3000 mg per day and less than or equal to 70 mg/kg/d.
  • the pharmaceutical composition is administered parenterally.
  • the redox-balancing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine in the pharmaceutical composition to be administered parenterally that is in the second container is about 200 mg NAC to about 20000 mg NAC per dosage unit.
  • the cystic fibrosis therapeutic agent in the first container is at least one agent selected from the group consisting of an anti-infective agent, a bronchodilating agent, and an anti-inflammatory agent.
  • condition refers to a variety of health states and is meant to include disorders or diseases caused by any underlying mechanism or disorder, injury, and the promotion of healthy tissues and organs.
  • disease or “disorder” as used herein refers to an impairment of health or a condition of abnormal functioning.
  • disorder refers to a pattern of symptoms indicative of some disease or condition.
  • modulate or “modulating” refers to adjusting, changing, or manipulating the function or status of at least one of redox balance or inflammation in cystic fibrosis. Such modulation may be any change, including an undetectable change.
  • a method of treating an inflammation in cystic fibrosis patients comprises the steps of administering to a patient in need thereof a composition comprising an inflammation-reducing amount of NAC, a pharmaceutically acceptable salt of NAC, or a pharmaceutically acceptable derivative of NAC, and a pharmaceutically acceptable carrier and a pharmaceutically acceptable carrier, thereby modulating the inflammation.
  • the term “treating” includes abrogating, substantially slowing or reversing the progression of a condition, substantially ameliorating clinical or symptoms of a condition, and substantially preventing the appearance of clinical or symptoms of a condition.
  • the term "inflammation” as used herein refers to the physiologic process by which vascularized tissues respond to injury. See, e.g., FUNDAMENTAL IMMUNOLOGY, 4 th Ed., William E. Paul, ed. Lippincott-Raven Publishers, Philadelphia (1999) at 1051-1053, incorporated herein by reference. During the inflammatory process, cells involved in detoxification and repair are mobilized to the compromised site by inflammatory mediators.
  • Inflammation is often characterized by a strong infiltration of leukocytes at the site of inflammation, particularly neutrophils (polymorphonuclear cells). These cells promote tissue damage by releasing toxic substances at the vascular wall or in uninjured tissue.
  • neutrophils polymorphonuclear cells
  • inflammation has been divided into acute and chronic responses.
  • the term "acute inflammation” as used herein refers to the rapid, short-lived (minutes to days), relatively uniform response to acute injury characterized by accumulations of fluid, plasma proteins, and neutrophilic leukocytes.
  • injurious agents that cause acute inflammation include, but are not limited, to pathogens (e.g., bacteria, viruses, parasites), foreign bodies from exogenous (e.g.
  • Chronic inflammation takes over when acute inflammation persists, either through incomplete clearance of the initial inflammatory agent or as a result of multiple acute events occurring in the same location.
  • the term "chronic inflammation” as used herein refers to inflammation that is of longer duration and which has a vague and indefinite termination. Chronic inflammation, which includes the influx of lymphocytes and macrophages and fibroblast growth, may result in tissue scarring at sites of prolonged or repeated inflammatory activity.
  • oxidative stress refers to a condition caused by an imbalance between reactive oxygen species and the antioxidant defense mechanisms of a cell, leading to an excess production of oxygen metabolites. Skaper, et al., Free Radical Biol. & Med. 22(4): 669-678 (1997).
  • redox imbalance refers to the imbalance between reactive oxygen species and the antioxidant defense mechanisms of a cell.
  • a method of treating a redox imbalance condition in cystic fibrosis patients comprises the steps of administering to a patient in need thereof a composition comprising a redox-balancing amount of NAC, a pharmaceutically acceptable salt of NAC, or a pharmaceutically acceptable derivative of NAC, and a pharmaceutically acceptable carrier and a pharmaceutically acceptable carrier, thereby modulating the redox imbalance condition.
  • a composition comprising a redox-balancing amount of NAC, a pharmaceutically acceptable salt of NAC, or a pharmaceutically acceptable derivative of NAC, and a pharmaceutically acceptable carrier and a pharmaceutically acceptable carrier, thereby modulating the redox imbalance condition.
  • the inflammation-reducing, redox imbalance adjusting or pharmaceutical effect can be curing, minimizing, preventing or ameliorating a disease or disorder, or may have any other anti-inflammatory, redox balancing or pharmaceutical beneficial effect.
  • concentration of the substance is selected so as to exert its inflammation-reducing, redox balancing, or pharmaceutical effect, but low enough to avoid significant side effects within the scope and sound judgment of the physician.
  • the effective amount of the composition may vary with the age and physical condition of the biological subject being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the specific compound, composition or other active ingredient employed, the particular carrier utilized, and like factors.
  • a skilled artisan can determine a pharmaceutically effective amount of the inventive compositions by determining the dose in a dosage unit (meaning unit of use) that elicits a given intensity of effect, hereinafter referred to as the "unit dose.”
  • dose-intensity relationship refers to the manner in which the intensity of effect in an individual recipient relates to dose.
  • the intensity of effect generally designated is 50% of maximum intensity.
  • the corresponding dose is called the 50% effective dose or individual ED50.
  • the use of the term “individual” distinguishes the ED50 based on the intensity of effect as used herein from the median effective dose, also abbreviated ED50, determined from frequency of response data in a population.
  • Effectiveness refers to the property of the compositions of the present invention to achieve the desired response, and “maximum efficacy” refers to the maximum achievable effect.
  • the amount of the NAC compounds in the compositions of the present invention which will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. (See, for example, Goodman and Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Joel G. Harman, Lee E.
  • compositions according to the present invention contain from about at least about 200 mg NAC to about 2000 mg NAC per dosage unit for oral administration.
  • the minimum pharmaceutically effective amount of NAC, pharmaceutically effective salts of NAC, or pharmaceutically acceptable NAC derivatives per dosage unit for oral administration according to the present invention is at least about: 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg
  • the maximum pharmaceutically effective amount of NAC, pharmaceutically effective salts of NAC, or pharmaceutically acceptable NAC derivatives per dosage unit for oral administration according to the present invention is no more than about: 2000 mg, 1900 mg, 1800 mg, 1700 mg, 1600 mg, 1500 mg, 1400 mg, 1300 mg, 1200 mg, 1100 mg, 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 400 mg, 300 mg, or 200 mg.
  • the pharmaceutical compositions according to the present invention contain from about at least about 200 mg NAC to about 20000 mg NAC per dosage unit for parenteral administration at the physician's discretion.
  • the minimum pharmaceutically effective amount of NAC, pharmaceutically effective salts of NAC, or pharmaceutically acceptable NAC derivatives per dosage unit for parenteral administration according to the present invention is at least about: 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg, 5000 mg, 5500 mg, 6000 mg, 6500 mg, 7000 mg, 7500 mg, 8000 mg, 8500 mg, 9000 mg, 9500 mg, 10000 mg, 11000 mg, 12000 mg, 13000 mg, 14000 mg, 15000 mg, 16000 mg, 17000 mg, 18000 mg, 19000 mg, or
  • Usual dosage should be about 1.8 grams per day ("g/d") to about 6.0 g/d (i.e., a minimum of about: 1.8, 1.9, 2.0, 2.1, 2,2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4,
  • the unit oral dose of NAC usually will comprise at least about 200 mg (for pediatric doses), usually at least about 600 mg (for adult doses); and usually not more than about 2000 mg at the physician's discretion, from a minimum of one to a maximum of six daily intakes. Patients on therapy known to deplete cysteine/glutathione or produce oxidative stress may benefit from higher amounts of NAC.
  • drug carrier refers to carrier materials suitable for NAC administration.
  • carrier and “pharmaceutical carrier” refer to a pharmaceutically acceptable inert agent or vehicle for delivering one or more active agents to a mammal, and often is referred to as "excipient.”
  • a pharmaceutically acceptable carrier refers to any substantially nontoxic carrier conventionally useable for NAC administration in which NAC will remain stable and bioavailable.
  • the (pharmaceutical) carrier must be of sufficiently high purity and of sufficiently low toxicity to render it suitable for administration to the mammal being treated.
  • the (pharmaceutical) carrier further should maintain the stability and bioavailability of an active agent, e.g., a signal transduction modulator compound of the present invention.
  • the (pharmaceutical) carrier can be liquid or solid and is selected, with the planned manner of administration in mind, to provide for the desired bulk, consistency, etc., when combined with an active agent and other components of a given composition.
  • the (pharmaceutical) carrier can be, without limitation, a binding agent (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.), a filler (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates, calcium hydrogen phosphate, etc.), a lubricant (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.), a disintegrant (e.g., starch, sodium starch glycolate, etc.), or a wetting agent (e.g., sodium lauryl sulfate, etc.).
  • a binding agent e.g., pregelatinized maize star
  • compositions of the present invention include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatins, amyloses, magnesium stearates, talcs, silicic acids, viscous paraffins, hydroxymethylcelluloses, polyvinylpyrrolidones and the like.
  • Compositions of the present invention that are for cutaneous administration, such as topical (i.e., local) can include (pharmaceutical) carriers such as sterile and non-sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of NAC in liquid or solid oil bases.
  • compositions of the present invention that are for parenteral administration of the signal transduction modulator compound, such as intramuscular or subcutaneously, can include (pharmaceutical) carriers such as sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of NAC in a liquid oil base.
  • the carrier of the composition of the present invention includes a release agent such as sustained release or delayed release carrier.
  • the carrier can be any material capable of sustained or delayed release of NAC to provide a more efficient administration, e.g., resulting in less frequent and/or decreased dosage of NAC, improve ease of handling, and extend or delay effects on diseases, disorders, conditions, syndromes, and the like, being treated, prevented or promoted.
  • Non-limiting examples of such carriers include liposomes, microsponges, microspheres, or microcapsules of natural and synthetic polymers and the like. Liposomes may be formed from a variety of phospholipids such as cholesterol, stearylamines or phosphatidylcholines.
  • compositions and methods of the present invention can be used in combination with known cystic fibrosis therapeutic agents, provided that they are compatible with each other.
  • compositions and methods of the present invention are capable of being combined with existing therapies in a manner such that there is no interaction that would substantially reduce the efficacy of either the compositions or methods of the present invention or the therapies under ordinary use conditions.
  • cystic fibrosis therapeutic agents that may be combined with the compositions and methods of the present invention include, but are not limited to, anti- infective agents, bronchodilating agents, and anti-inflammatory agents.
  • Lung and airway infections in cystic fibrosis can be treated with potent anti-infective agents, including antibiotics, to improve lung function, reduce days spent in the hospital and to reduce use of intravenous antibiotics to reduce bacterial levels in the lungs. Inhaled antibiotics also are used to prevent lung infections that may lead to hospitalization.
  • bronchodilating agents often are used along with inhaled antibiotics.
  • Bronchodilating agents are used widely for treating a variety of obstructive lung diseases, including cystic fibrosis. They relax smooth muscle in the small airways of the lungs, which dilates the airways and makes breathing easier, particularly when airways are narrowed by inflammation. Inhaled bronchodilator medications used in asthma, such as albuterol, have improved breathing in some people with cystic fibrosis. When used to treat cystic fibrosis, bronchodilating agents are usually given through a nebulizer or with a handheld inhaler. Airway dilatation before physiotherapy helps the cystic fibrosis patient to clear chest secretions.
  • Nonsteroidal anti-inflammatory agents reduce inflammation and pain. Cystic fibrosis patients often have persistent lung inflammation which becomes part of the cycle of continued lung damage in these patients. Anti-inflammatory medications, such as ibuprofen, in some patients with CF help to reduce this inflammation. In some children, antiinflammatory medications can significantly slow the progression of lung disease and improve breathing.
  • compositions and methods of the present invention can be used in combination with known cystic fibrosis therapies, provided that they are compatible with each other.
  • the term "respiratory therapy” as used herein refers to chest physiotherapy, which is used to help clear excess mucus out of the lungs.
  • chest physiotherapy To perform chest physiotherapy, a patient is placed in various positions allowing major segments of the lungs to point downward and then clapped firmly over chest and back on part of the lung segment to shake the mucus loose. Once loosened, the mucus will fall to the large airways, where it can be coughed out. Chest physiotherapy can be time-consuming since 3-5 minutes is spent clapping over 10-12 lung segments. It also is difficult for patients to perform on themselves and usually requires a skilled caregiver.
  • the term "rehabilitative therapy” refers to a therapy designed to help cystic fibrosis patients use their energy more efficiently, i.e., in a way that requires less oxygen. Rehabilitative therapy improves shortness of breath and overall survival, especially in those with advanced disease.
  • the NAC be substantially free of sulfones or other chemicals that interfere with the metabolism of any co-administered drug in its bioactive form. It is also preferred that the NAC be substantially free of its oxidized form, di-N-acetylcysteine, and that the composition should be prepared in a manner that substantially prevents oxidation of the NAC during preparation or storage.
  • a typical unit dosage may be a solution suitable for oral or intravenous administration; an effervescent tablet suitable for dissolving in water, fruit juice, or carbonated beverage and administered orally; a tablet taken from two to six times daily, or one time-release capsule or tablet taken several times a day and containing a proportionally higher content of active ingredient, etc.
  • the time-release effect may be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.
  • Unit dosage forms may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, gel capsule, tablet or suppository, contains a predetermined amount of the compositions of the present invention.
  • unit dosage forms for injection or intravenous administration may comprise the compound of the present invention in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.
  • the specifications for the unit dosage forms of the present invention depend on the effect to be achieved and the intended recipient.
  • NAC Over-the-counter NAC can be variably produced and packaged. Because the production and packaging methods generally do not guard against oxidation, the NAC can be significantly contaminated with bioactive oxidation products. These may be particularly important in view of data indicating that the oxidized form of NAC has effects counter to those reported for NAC and is bioactive at doses roughly 10-100 fold less than NAC. See Sarnstrand et al J. Pharmacol. Exp. Ther. 288:1174-84 (1999). [0056] The distribution of the oxidation states of NAC as a thiol and disulfide depends on the oxidation/reduction (redox) potential.
  • redox oxidation/reduction
  • the half-cell potential obtained for the NAC thiol/disulfide pair is about +63 mV, indicative of its strong reducing activity among natural compounds [see Noszal et al. J. Med. Chem. 43:2176-2182 (2000)].
  • the preparation and storage of the formulation is performed in such a way that the reduced form of NAC is the primary form administered to the patient. Maintaining NAC containing formulations in solid form is preferable for this purpose. When in solution, NAC containing formulations are preferably stored in a brown bottle that is vacuum sealed. Storage in cool dark environments is also preferred.
  • compositions of the present invention may be administered systemically either orally, buccally, parenterally, topically, by inhalation or insufflation (i.e., through the mouth or through the nose), or rectally in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • compositions of the present invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient(s) in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They also may be coated for controlled release.
  • compositions of the present invention also may be formulated for oral use as hard gelatin capsules, where the active ingredient(s) is(are) mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules wherein the active ingredient(s) is (are) mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • compositions of the present invention maybe formulated as aqueous suspensions wherein the active ingredient(s) is (are) in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl- eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide
  • compositions of the present invention may be formulated as oily suspensions by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • compositions of the present invention may be formulated in the form of dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water.
  • the active ingredient in such powders and granules is provided in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives.
  • a dispersing or wetting agent, suspending agent, and one or more preservatives are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents also may be present.
  • compositions of the invention also may be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth, naturally-occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • compositions of the invention also may contain sweetening and flavoring agents.
  • the compositions of the invention also may be formulated as syrups and elixirs. Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations also may contain a demulcent, a preservative, and flavoring and coloring agents. Demulcents are protective agents employed primarily to alleviate irritation, particularly mucous membranes or abraded tissues. A number of chemical substances possess demulcent properties. These substances include the alginates, mucilages, gums, dextrins, starches, certain sugars, and polymeric polyhydric glycols.
  • Others include acacia, agar, benzoin, carbomer, gelatin, glycerin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, propylene glycol, sodium alginate, tragacanth, hydrogels and the like.
  • compositions of the present invention may take the form of tablets or lozenges formulated in a conventional manner.
  • compositions of the present invention may be in the form of a sterile injectable aqueous or oleaginous suspension.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • injectable preparations such as sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution, hi addition, sterile, fixed oils are employed conventionally as a solvent or suspending medium.
  • suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants.
  • Aqueous suspensions may contain substances which increase the viscosity of the suspension and include, for example, sodium carboxymethyl cellulose, sorbitol and/or dextran.
  • the suspension may also contain stabilizers.
  • Topical refers to administration of an inventive composition at, or immediately beneath, the point of application.
  • topically applying describes application onto one or more surfaces(s) including epithelial surfaces.
  • topical administration in contrast to transdermal administration, generally provides a local rather than a systemic effect, as used herein, unless otherwise stated or implied, the terms topical administration and transdermal administration are used interchangeably.
  • topical applications shall include mouthwashes and gargles.
  • Topical administration also may involve the use of transdermal administration such as transdermal patches or iontophoresis devices, which are prepared according to techniques and procedures well known in pharmacology.
  • transdermal delivery system transdermal patch or “patch” refer to an adhesive system placed on the skin to deliver a time released dose of a drug(s) by passage from the dosage form through the skin to be available for distribution via the systemic circulation.
  • Transdermal patches are a well-accepted technology used to deliver a wide variety of pharmaceuticals, including, but not limited to, scopolamine for motion sickness, nitroglycerin for treatment of angina pectoris, clonidine for hypertension, estradiol for post-menopausal indications, and nicotine for smoking cessation.
  • Patches suitable for use in the present invention include, but are not limited to (1) the matrix patch; (2) the reservoir patch; (3) the multi-laminate drug-in-adhesive patch; and (4) the monolithic drug-in-adhesive patch TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS, pp. 249-297 (Tapash K. Ghosh et al. eds., 1997), hereby incorporated herein by reference. These patches are well known in the art and generally available commercially.
  • the compositions of the present invention maybe in the form of a dispersible dry powder for pulmonary delivery. Dry powder compositions may be prepared by processes known in the art as disclosed in U.S. Pat. No.
  • Spray drying is a process in which a homogeneous aqueous mixture of drug and the carrier is introduced via a nozzle (e.g., a two fluid nozzle), spinning disc or an equivalent device into a hot gas stream to atomize the solution to form fine droplets.
  • the aqueous mixture maybe a solution, suspension, slurry, or the like, but needs to be homogeneous to ensure uniform distribution of the components in the mixture and ultimately the powdered composition.
  • the solvent generally water, rapidly evaporates from the droplets producing a fine dry powder having particles from about 1 ⁇ m to 5 ⁇ m in diameter.
  • the spray drying is done under conditions that result in a substantially amorphous powder of homogeneous constitution having a particle size that is respirable, a low moisture content and flow characteristics that allow for ready aerosolization.
  • the particle size of the resulting powder is such that more than about 98% of the mass is in particles having a diameter of about 10 ⁇ m or less with about 90% of the mass being in particles having a diameter less than 5 ⁇ m.
  • about 95% of the mass will have particles with a diameter of less than 10 ⁇ m with about 80% of the mass of the particles having a diameter of less than 5 ⁇ m.
  • Dry powder compositions also may be prepared by lyopbilization and jet milling, as disclosed in International Patent Publication No. WO 91/16038, the disclosure of which are incorporated by reference.
  • the term "dispersibility” or “dispersible” means a dry powder having a moisture content of less than about 10% by weight (% w) water, usually below about 5% w and preferably less than about 3% w; a particle size of about 1.0-5.0 ⁇ m mass median diameter (MMD), usually 1.0-4.0 ⁇ m MMD, and preferably 1.0-3.0 ⁇ m MMD; a delivered dose of about >30%, usually >40%, preferably >50%, and most preferred >60%; and an aerosol particle size distribution of about 1.0-5.0 ⁇ m mass median aerodynamic diameter (MMAD), usually 1.5-4.5 ⁇ m MMAD, and preferably 1.5-4.0 ⁇ m MMAD.
  • MMD mass median diameter
  • MMAD aerodynamic diameter
  • the term "powder” means a composition that consists of finely dispersed solid particles that are free flowing and capable of being readily dispersed in an inhalation device and subsequently inhaled by a subject so that the particles reach the lungs to permit penetration into the alveoli.
  • the powder is said to be "respirable.”
  • the average particle size is less than about 10 microns ( ⁇ m) in diameter with a relatively uniform spheroidal shape distribution. More preferably the diameter is less than about 7.5 ⁇ m and most preferably less than about 5.0 ⁇ m.
  • the particle size distribution is between about 0.1 ⁇ m and about 5 ⁇ m in diameter, particularly about 0.3 ⁇ m to about 5 ⁇ m.
  • dry means that the composition has a moisture content such that the particles are readily dispersible in an inhalation device to form an aerosol. This moisture content is generally below about 10% by weight (% w) water, usually below about 5% w and preferably less than about 3% w.
  • the amount of the pharmaceutically acceptable carrier is that amount needed to provide the necessary stability, dispersibility, consistency and bulking characteristics to ensure a uniform pulmonary delivery of the composition to a subject in need thereof. Numerically the amount may be from about 0.05% w to about 99.95% w, depending on the activity of the drug being employed. Preferably about 5% w to about 95% will be used.
  • the carrier may be one or a combination of two or more pharmaceutical excipients, but generally will be substantially free of any "penetration enhancers.” Penetration enhancers are surface active compounds which promote penetration of a drug through a mucosal membrane or lining and are proposed for use in intranasal, intrarectal, and intravaginal drug formulations.
  • Exemplary penetration enhancers include bile salts, e.g., taurocholate, glycocholate, and deoxycholate; fusidates, e.g., taurodehydrofusidate; and biocompatible detergents, e.g., Tweens, Laureth-9, and the like.
  • bile salts e.g., taurocholate, glycocholate, and deoxycholate
  • fusidates e.g., taurodehydrofusidate
  • biocompatible detergents e.g., Tweens, Laureth-9, and the like.
  • the dry powder compositions of the present invention are readily absorbed in the lungs without the need to employ penetration enhancers.
  • the types of pharmaceutical excipients that are useful as carriers for pulmonary delivery include stabilizers such as human serum albumin (HSA), bulking agents such as carbohydrates, amino acids and polypeptides; pH adjusters or buffers; salts such as sodium chloride; and the like. These carriers may be in a crystalline or amorphous form or may be a mixture of the two.
  • HSA human serum albumin
  • bulking agents such as carbohydrates, amino acids and polypeptides
  • pH adjusters or buffers such as sodium chloride
  • salts such as sodium chloride
  • Bulking agents that are particularly valuable for pulmonary delivery include compatible carbohydrates, polypeptides, amino acids or combinations thereof.
  • suitable carbohydrates include monosaccharides such as galactose, D-mannose, sorbose, and the like; disaccharides, such as lactose, trehalose, and the like; cyclodextrins, such as 2- hydroxypropyl-/3-cyclodextrin; and polysaccharides, such as raffmose, maltodextrins, dextrans, and the like; alditols, such as mannitol, xylitol, and the like.
  • a preferred group of carbohydrates includes lactose, trehalose, raffinose, maltodextrins, and mannitol.
  • Suitable polypeptides include aspartame.
  • Amino acids include alanine and glycine, with glycine being preferred.
  • Additives which are minor components of the composition for pulmonary delivery, may be included for conformational stability during spray drying and for improving dispersibility of the powder.
  • additives include hydrophobic amino acids such as tryptophan, tyrosine, leucine, phenylalanine, and the like.
  • Suitable pH adjusters or buffers include organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, and the like; sodium citrate is preferred.
  • the composition of the present invention is placed within a suitable dosage receptacle in an amount sufficient to provide a subject with a unit dosage treatment.
  • the dosage receptacle is one that fits within a suitable inhalation device to allow for the aerosolization of the dry powder composition by dispersion into a gas stream to form an aerosol and then capturing the aerosol so produced in a chamber having a mouthpiece attached for subsequent inhalation by a subject in need of treatment.
  • Such a dosage receptacle includes any container enclosing the composition known in the art such as gelatin or plastic capsules with a removable portion that allows a stream of gas (e.g., air) to be directed into the container to disperse the dry powder composition.
  • a stream of gas e.g., air
  • Such containers are exemplified by those shown in U.S. Pat. Nos. 4,227,522; U.S. Pat. No. 4,192,309; and U.S. Pat. No. 4,105,027.
  • Suitable containers also include those used in conjunction with Glaxo's Ventolin® Rotohaler brand powder inhaler or Fison's Spinhaler® brand powder inhaler.
  • Another suitable unit-dose container which provides a superior moisture barrier is formed from an aluminum foil plastic laminate.
  • the pharmaceutical-based powder is filled by weight or by volume into the depression in the formable foil and hermetically sealed with a covering foil-plastic laminate.
  • a container for use with a powder inhalation device is described in U.S. Pat. No. 4,778,054 and is used with Glaxo's Diskhaler® (U.S. Pat. Nos. 4,627,432; 4,811,731; and 5,035,237). All of these references are incorporated herein by reference.
  • the compositions of the present invention may be in the form of suppositories for rectal administration of the composition.
  • compositions can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • the compositions of the invention may be formulated with traditional binders and carriers, such as triglycerides.
  • the therapeutically active agent of the present invention can be formulated per se or in salt form.
  • pharmaceutically acceptable salts refers to nontoxic salts of NAC.
  • Pharmaceutically acceptable salts include, but are not limited to, those formed with free amino groups such as those derived from hydrochloric, phosphoric, sulfuric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2- ethylamino ethanol, histidine, procaine, etc.
  • N-acetylcysteine derivative refers to a pharmaceutically acceptable compound formed from N-acetylcysteine or a pharmaceutically acceptable compound that can be imagined to arise from N-acetylcysteine if one atom is replaced with another atom or group of atoms.
  • compositions of the present invention can be readily prepared using technology which is known in the art such as described in Remington 's Pharmaceutical Sciences, 18 th or 19 th editions, published by the Mack Publishing Company of Easton, Pennsylvania, which is incorporated herein by reference.
  • the present invention further provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • a pharmaceutical kit for treating lung inflammation in cystic fibrosis patients includes a first container containing a pharmaceutically effective amount of a cystic fibrosis therapeutic agent and a second container containing a pharmaceutical composition comprising an inflammation- reducing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine, and a pharmaceutically acceptable carrier.
  • a pharmaceutical kit for treating redox imbalance in cystic fibrosis patients includes a first container containing a pharmaceutically effective amount of a cystic fibrosis therapeutic agent and a second container containing a pharmaceutical composition comprising a redox-balancing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N-acetylcysteine, and a pharmaceutically acceptable carrier.
  • a pharmaceutical kit for treating inflammation and redox imbalance in cystic fibrosis patients includes a first container filled with a pharmaceutically effective amount of a cystic fibrosis therapeutic agent and a second container filled with a pharmaceutical composition comprising an inflammation-reducing and redox-balancing amount of N-acetylcysteine, a pharmaceutically acceptable salt of N-acetylcysteine, or a pharmaceutically acceptable derivative of N- acetylcysteine, and a pharmaceutically acceptable carrier.
  • Example I Treatment of cystic fibrosis patients with oral N-acetylcysteine
  • a phase I trial of high-dose oral N-acetylcysteine (NAC) in CF has been completed.
  • This CF Foundation-sponsored dose-escalation safety pilot study was designed to assess the dose of oral NAC that can be used safely in order to replenish glutathione (GSH) stores in subjects with CF, with the objectives of restoring a proper redox balance and limiting lung inflammation in patients.
  • GSH glutathione
  • HPLC HPLC
  • GSH live blood neutrophil GSH
  • Lung inflammation as reflected chiefly by (i) sputum counts in total live leukocytes and neutrophils (along with % neutrophils in sputum); (iii) plasma / sputum levels of elastase and interleukin-8 (IL-8) measured by spectrophotometry and ELISA (BD Biosciences, San Diego, CA, USA); and [00102] 3. Lung function, as measured by spirometry.
  • Example 2 Phase II placebo-controlled clinical trial of high-dose oral N- acetylcysteine in CF.
  • phase II trial consists of a 12-wk placebo controlled portion, followed by a 12-wk open label portion, both featuring oral NAC treatment at about
  • CF lung disease is characterized by the progressive decline in functional expiratory volume in 1 second (FEV1% predicted).
  • FEV1% refers to Forced Expiratory Volume during the first second/FVC, where FVC refers to Forced (Expiratory Vital Capacity (Liters), meaning the maximum volume of air exhaled as rapidly, forcefully and completely as possible from the point of maximum inhalation. Slowing down, stopping or reversing this decline reflect positive effects of a treatment, which generally requires long-term administration.

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  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Cette invention concerne des trousses pharmaceutiques et des méthodes permettant de traiter une inflammation du poumon et un déséquilibre d'oxydoréduction chez des patients humains atteints de mucoviscidose à l'aide de compositions pharmaceutiques contenant une N-acétylcystéine (NAC), des sels pharmaceutiquement acceptables de N-acétylcystéine ou des dérivés de N-acétylcystéine. Dans les études de phase I, un traitement par administration par voie orale de N-acétylcystéine à raison d'environ 1800 mg/jour à environ 3000 mg/jour pendant 4 semaines produit des effets positifs importants et permet plus précisément de réduire les nombres absolus de globules blancs et de neutrophiles dans l'expectoration et de réduire simultanément l'activité spécifique de l'élastase neutrophile de l'expectoration et les niveaux d'interleukine-8 de l'expectoration, suggérant ainsi une amélioration de l'inflammation du poumon chez les patients. Ces effets sont associés à une augmentation du niveau de GSH total dans le sang ainsi qu'à une augmentation de la coloration pour réduction de GSH dans les neutrophiles sanguins, ce qui reflète une amélioration du déséquilibre d'oxydoréduction chez les patients. Dans les études de phase II en cours, l'administration par voie orale de N-acétylcystéine à raison d'environ 2700 mg/jour selon un essai à double insu pendant douze semaines a présenté une excellente innocuité et une réduction considérable du nombre de globules blancs dans l'expectoration comparé au placebo.
PCT/US2006/032809 2005-08-24 2006-08-22 Methodes de traitement et de surveillance de l'inflammation et du desequilibre d'oxydoreduction dans la mucoviscidose WO2007024876A2 (fr)

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US9308234B2 (en) 2012-10-29 2016-04-12 The University Of North Carolina At Chapel Hill Methods and compositions for treating mucosal tissue disorders
US11497786B2 (en) 2017-11-17 2022-11-15 Renovion, Inc. Stable ascorbic acid compositions and methods of using the same
US11602555B2 (en) 2016-11-17 2023-03-14 Renovion, Inc. Treatment of respiratory tract diseases and infections with ascorbic acid compositions
US12097238B2 (en) 2022-01-04 2024-09-24 Renovion, Inc. Aqueous solution comprising a glutathione salt

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US9308234B2 (en) 2012-10-29 2016-04-12 The University Of North Carolina At Chapel Hill Methods and compositions for treating mucosal tissue disorders
US10406200B2 (en) 2012-10-29 2019-09-10 The University Of North Carolina At Chapel Hill Methods and compositions for treating mucusal tissue disorders
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US11602555B2 (en) 2016-11-17 2023-03-14 Renovion, Inc. Treatment of respiratory tract diseases and infections with ascorbic acid compositions
US11497786B2 (en) 2017-11-17 2022-11-15 Renovion, Inc. Stable ascorbic acid compositions and methods of using the same
US11890315B2 (en) 2017-11-17 2024-02-06 Renovion, Inc. Stable ascorbic acid compositions and methods of using same
US12097238B2 (en) 2022-01-04 2024-09-24 Renovion, Inc. Aqueous solution comprising a glutathione salt

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WO2007024876A3 (fr) 2007-09-20
CA2620123C (fr) 2011-11-22
US20070049641A1 (en) 2007-03-01

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